Previously approved drugs may be helpful in fatal pediatric disorder

A progressive neurodegenerative disorder that is often fatal within the first two decades of life may be treatable via a molecule already targeted by approved drugs, scientists at Washington University School of Medicine in St. Louis and other institutions report.

Scientists working with a mouse model for Niemann-Pick type C (NPC) disease showed that experimental treatments appear to be acting through the pregnane X receptor (PXR). Found in the cell nucleus, PXR regulates the activity of a cluster of genes that helps the body get rid of toxins.

NPC affects approximately one in every 100,000 children. Affected individuals typically present in early childhood with gait disturbance and progressive impairment of motor and intellectual function and usually die during adolescence. At present there are no effective treatment options.

Drugs already known to activate PXR include the anti-seizure drug dilantin, the antibiotic rifampicin and the herbal compound St. John's Wort. Additional experiments are underway in mice to firmly determine if the successful laboratory treatments are acting through PXR. If this proves to be the case, new clinical trials may soon follow, according to senior author Daniel S. Ory, M.D., associate professor of medicine and of cell biology and physiology.

"Because we have so few options to offer NPC patients and their families now, if this connection can be confirmed, we'd try to get some known activators of PXR into clinical trials as soon as possible," Ory says.

The results appear online this week in the Proceedings of the National Academy of Sciences.

NPC belongs to a broader class of diseases known as lysosomal storage disorders, which affect more than 30,000 people worldwide. In these disorders, disposal and recycling units within cells known as lysosomes become jammed, preventing proper degradation of certain compounds and leading them to build up to dangerous levels.

In NPC, the molecule that builds up in the lysosomes is cholesterol. Cells use compounds made from cholesterol to sense and regulate their own internal cholesterol level. The jam in the lysosomes disrupts creation of these byproducts, impairing the cell's ability to sense its own cholesterol levels. As a result, cells continue to make and take in cholesterol even after their cholesterol levels are already dangerously high.

This buildup has toxic effects on an important class of brain cells known as Purkinje cells. As they die off, patient function progressively declines.

"The learning difficulty is the most obvious indicator, but some symptoms are often very insidious in the early stages of the disorder," Ory says. "It's unfortunately not a disease that many primary care physicians are looking for, and I suspect it may be seriously underdiagnosed."

In 1980, researchers identified a mouse line with a mutation that naturally duplicated the pathology seen in human NPC. They have since used it as a model of the disorder.

With the support of the Ara Parseghian Medical Research Foundation, a private foundation established in 1994 to fund NPC research, scientists in 1997 linked most forms of NPC to a gene they named npc1. Through grants from the same foundation, Ory's research group has been studying how npc1 changes affect cholesterol metabolism.

For the new study, scientists in Ory's lab were using the mouse model of NPC to test a synthetic compound that activated genes for proteins that break down cholesterol and remove it from cells. At the same time, Synthia H. Mellon, Ph.D., of the University of California-San Francisco, was treating the same mouse line with a naturally occurring nervous system steroid similar to the cholesterol sensors used by healthy cells.

Both efforts met with moderate success. When the labs combined the treatments, though, a single dose 7 days after birth extended the average mouse lifespan from 78.8 days to 135.7 days, or 72 percent.

After an extensive search for indications of how the experimental treatments might be working, scientists found increases in the activity of a gene regulated by PXR. Ory believes that the genes activated by PXR may help cells break down toxic byproducts of excessive cholesterol buildup.

Researchers determined that both of the treatments they used can activate PXR. To establish definitive proof of the link between PXR and successful treatment of NPC, they have now created a mouse line that has the NPC disorder but also lacks the gene for PXR. If the treatments do not help those mice, the link will be confirmed, and scientists will begin considering the treatment possibilities offered by approved drugs known to affect PXR.

Funding from the Ara Parseghian Medical Research Foundation supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Last reviewed:
By John M. Grohol, Psy.D. on
21 Feb 2009
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